Stochastic Simulations

Shen Cheng

2024-11-08

Drug X

  • Drug X is a small molecule drug under early-phase clinical investigation to treat Disease Y in pediatric patients (age 2-18 years).

  • An phase-I single ascending dose (SAD) clinical study has been completed to investigate the PK of drug X, with 50 patients receiving 1, 2, 5, 10 and 20 mg dose of drug X.

  • A population PK model was developed using these PK data (./wk8/model/hwwk6.mod).

  • Some efficacy related endpoints were also collected and the clinical team are interested in exploring exposure-response relationships.

Exercise 1: Stochastic Simulation

  • The study team is now designing a Phase 2 proof of concept (POC) study, which they plan to use a twice daily dose (BID) dosing. They want to understand what dosage levels are appropriate to test.

  • Preclinical study shows:

    • IC90 of drug X is 1 ug/L.
    • Drug X concentration above 15 ug/L is associated with dose-limit toxicity.

Exercise 1: Question

Considering steady-state is achieve after 4 days with BID dosing. The study team is wondering:

  • At what dose level can we achieve a steady-state Cmin > 1 ug/L in > 80% patients.

  • At what dose level can we maintain a steady-state Cmax > 15 ug/L in < 20% patients.

Workflow-Stochastic Simulations

Workflow-Stochastic Simulations

Hands-on Session: Exercise 1

Files:

  • wk10/model/hwwk6.mod: mrgsolve model for Drug X.
  • wk10/ex1.R: R script to implement simulation.
  • wk10/data/pop.csv: population covariate for simulation.

Implementation notes:

  • Don’t need residual variability in simulation (mod <- mod %>% zero_re(sigma)).
  • Use wk10/data/pop.csv for population covariates.
  • Use addl and ii to implement multiple dosing (e.g., BID).
  • Weight-based dosing.
  • Need to have rate=-2 to enable the use of dosing duration (D1) in the model.

Hands-on Session: Exercise 1

Hands-on Session: Exercise 1 Cmin

Hands-on Session: Exercise 1 Cmin

Hands-on Session: Exercise 1 Cmin

Hands-on Session: Exercise 1 Cmin